Abstract 2007: MHC class I polypeptide related sequence A (MICA) in context of aggressive prostate cancer

Abstract

Abstract Prostate cancer (PCa) is the second most common cancer in American men, with higher incidence and death rates in African American men (AAM) relative to Caucasian American men (CAM). MHC class I polypeptide-related sequence A (MICA) is a protein expressed in the membrane of tumor cells that binds to the NKG2D receptors in NK cells and subtypes of CD8+T cells, activating its cytotoxic effects. Aggressive tumors cleave MICA from the membrane, release the soluble form (sMICA) into the plasma and downregulate the NKG2D receptor from the immune cells. Reports in PCa show loss of MICA expression from the cell surface is associated to a more aggressive phenotype. Likewise, increased levels of sMICA were linked to patients with Gleason score (GS) greater than 7. We hypothesized that conditions related to tumor aggressiveness in the microenvironment, would modify the levels of MICA in PCa. We also speculated that, when compared to CAM, MICA would be differentially expressed in tumors from AAM. To access the different expression of MICA in AAM and CAM PCa patients we stained a TMA containing 41 CAM and 44 AAM tumor cores for MICA expression. Our results showed that CAM PCa tumor cores had higher proportion of high expression of MICA than the AAM (38% vs 7% respectively, p=0.008). Moreover, the association between race and MICA expression was more profound with GS greater than 7 (p=0.001). Next, we explored the effect of hypoxia, a condition known to be associated with tumor aggressiveness, on MICA surface expression. We stained our TMA for hypoxia-inducible factor 1-alpha (HIF1-α), the master regulator of cellular and developmental response to hypoxia. Similar to MICA expression, HIF1- α expression was observed in tumor cores compared to normal tissue cores (43% vs 17% respectively, p=0.021). In CAM there was a positive correlation between MICA and HIF1-α immunostaining (rs= 0.50, p= 0.004), while in AAM correlation was weak (rs= 0.32, p= 0.081). FACS analysis on C4-2B cells revealed that 1% O2 (hypoxia) reduced MICA expression by 24.1%, relative to 20% O2 (normoxia). Likewise, incubation of PCa cells in the presence of 100µM cobalt chloride, a compound that mimics hypoxia by inducing HIF-1/3 α, reduced MICA by 16.7%, relative to control conditions. Altogether, our results indicate that expression of MICA is modified by disease aggressiveness and hypoxic conditions. Experiments to validate our results in minorities are currently in progress. Of equal interest is the progress of experiments focused on elucidation of the mechanistic involvement of tumor microenvironment on MICA-mediated tumorigenesis and immunoevasion. Funding acknowledgements: PCRP W81XWH-14-1-0151 (CRG), UMMC Department of Pathology (CRG), CAPES (MJS). Citation Format: Marcelo J. Sakiyama, Ingrid Espinoza, Amit Reddy, Jack R. Lewin, Xinchun Zhou, Xu Zhang, Jesus Monico, Charles R. Pound, Christian R. Gomez. MHC class I polypeptide related sequence A (MICA) in context of aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2007. doi:10.1158/1538-7445.AM2017-2007